2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors

Marcello Allegretti, Riccardo Bertini, Maria Candida Cesta, Cinzia Bizzarri, Rosa Di Bitondo, Vito Di Cioccio, Emanuela Galliera, Valerio Berdini, Alessandra Topai, Giuseppe Zampella, Vincenzo Russo, Nicoletta Di Bello, Giuseppe Nano, Luca Nicolini, Massimo Locati, Piercarlo Fantucci, Saverio Florio, Francesco Colotta

Research output: Contribution to journalArticlepeer-review


The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCLS-induced human PMNs chemotaxis. We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1. The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity. Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.

Original languageEnglish
Pages (from-to)4312-4331
Number of pages20
JournalJournal of Medicinal Chemistry
Issue number13
Publication statusPublished - Jun 30 2005

ASJC Scopus subject areas

  • Organic Chemistry


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